Project Summary Genetic control of Programmed Cell Death in Drosophila Programmed cell death (apoptosis) is a physiological process of cell death that is critical for normal development and tissue homeostasis. Defects in the regulation of cell death mechanisms contribute to the pathogenesis of multiple diseases including those associated with reduced rates of cell death (cancer, autoimmunity) or with excessive cell death (neurodegeneration, stroke, myocardial infarction). The overall objective of our research is to gain a comprehensive understanding of the biological principles that underlie the regulation of cell death in the context of a multi-cellular organism, to identify and characterize the genes involved in this process, and to develop methods to manipulate them. Knowledge obtained in these studies will provide new insights into diseases that are associated with altered rates of apoptosis. We are using the genetic model organism Drosophila melanogaster in these studies. During Drosophila development many cells die by apoptosis. As in vertebrates, this cell death is not genetically predetermined in a lineage-restricted manner, but is dependent on environmental circumstances. Thus, Drosophila shares this developmental plasticity with vertebrates. Therefore, molecular genetic studies in Drosophila promise considerable potential for advancing our understanding of the basic control mechanisms involved in the regulation of apoptosis in vertebrates including humans. In the previous funding period we have performed genetic screens aimed at identifying genes involved in the control of programmed cell death. We have identified approximately 30 genes which directly or indirectly regulate cell death. It is the overall goal to characterize these genes phenotypically and molecularly, and to reveal their function for the control of programmed cell death. Finally, we wish to extend our screening efforts to the X chromosome which contains about 20% of the Drosophila genes. The characterization of these genes may have significant implications for the understanding of human diseases, and may help developing drugs and therapies to treat these diseases.